Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the spontaneous canine model of non-Hodgkin lymphoma

Sloan, Shelby; Renaldo, Kyle A.; Long, Mackenzie; Chung, Jin‐Tae; Courtney, Lindsay; Shilo, Konstantin; Schlotter, Sarah; Brown, Fiona; Klamer, Brett; Zhang, Xiaoli; Yilmaz, Ayse Selen; Özer, Hatice Gülçin; Valli, V. E.; Vaddi, Kris; Scherle, Peggy; Alinari, Lapo; Kisseberth, William C.; Baiocchi, Robert A.

doi:10.1371/journal.pone.0250839

Cited by 6 publications

(4 citation statements)

References 63 publications

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“…However, in vivo studies in mice indicated that these drugs did not arrest tumour growth, although the methylation in the target gene promoter was reduced [132]. Sloan et al, (2021) showed an overexpression of protein arginine methyltransferase 5 (PRMT5) in primary B-cell canine lymphomas, arguing that PRMT5 inhibitors could be a candidate as a new therapy in CML [133].…”

Section: Demethylation and Deacetylation Drugs As Treatment For Canin...mentioning

confidence: 99%

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

Montaner-Angoiti

Marín-García

Llobat

2023

Animals

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Canine malignant lymphoma is a common neoplasia in dogs, and some studies have used dogs as a research model for molecular mechanisms of lymphomas in humans. In two species, chemotherapy is the treatment of choice, but the resistance to conventional anticancer drugs is frequent. The knowledge of molecular mechanisms of development and progression of neoplasia has expanded in recent years, and the underlying epigenetic mechanisms are increasingly well known. These studies open up new ways of discovering therapeutic biomarkers. Histone deacetylases and demethylase inhibitors could be a future treatment for canine lymphoma, and the use of microRNAs as diagnosis and prognosis biomarkers is getting closer. This review summarises the epigenetic mechanisms underlying canine lymphoma and their possible application as treatment and biomarkers, both prognostic and diagnostic.

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Section: Demethylation and Deacetylation Drugs As Treatment For Canin...mentioning

confidence: 99%

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

Montaner-Angoiti

Marín-García

Llobat

2023

Animals

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“…45 Additionally, in vitro cultured canine lymphoma cells lines that overexpress PRTM5 have increased SDMA and have reductions in intracellular SDMA with PRMT5 inhibition. 43,46,47 To our knowledge, there have been no studies that evaluate both SDMA serum concentrations and concurrent tumour PRMT5 expression in humans, laboratory or pet animals. Further study would be needed to evaluate whether overproduction of SDMA by tumour tissue plays a role in the serum SDMA elevations seen in dogs and cats with lymphoma or other PRMT5 over-expressing tumours.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, over‐expression of PRMT5 in canine lymphoma tissues compared to normal or hyperplastic lymphoid tissue has also been demonstrated 45 . Additionally, in vitro cultured canine lymphoma cells lines that overexpress PRTM5 have increased SDMA and have reductions in intracellular SDMA with PRMT5 inhibition 43,46,47 . To our knowledge, there have been no studies that evaluate both SDMA serum concentrations and concurrent tumour PRMT5 expression in humans, laboratory or pet animals.…”

Section: Discussionmentioning

confidence: 99%

The association between symmetric dimethylarginine concentrations and various neoplasms in dogs and cats

Coyne

Drake

McCrann

et al. 2022

Vet Comparative Oncology

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Following the introduction of the symmetric dimethylarginine (SDMA) immunoassay, cases were reported where the SDMA concentration was markedly increased above the reference interval (RI) with neither concurrent increases in serum creatinine (Cr) concentrations nor clinical signs of kidney disease. Many of these animals were also concurrently diagnosed with cancer, most commonly lymphoma. The purpose of the study was to evaluate the association of increased SDMA in dogs and cats with lymphoma and other cancers as compared with age‐ and breed‐matched non‐tumour controls. In this retrospective case–control study, serum chemistry results from 1804 tumour cases, and age‐ and breed‐matched non‐tumour control animals were used. Matched‐pair odds ratios between animals diagnosed with neoplasms and non‐tumour controls for dichotomized SDMA values were determined by tumour type. SDMA concentrations were significantly higher in dogs and cats with lymphoma (p < .0001) compared with non‐tumour controls. The odds ratio for increased SDMA concentrations in dogs with lymphoma was 10.0 (95% CI, 5.98–16.72) and for cats with lymphoma was 3.04 (95% CI 1.95–4.73). A significant number of canine and feline lymphoma cases had an increased SDMA concentration not associated with an increased Cr concentration (p < .001). Canine and feline lymphoma patients have an increased odds of having a SDMA concentration above the RI at diagnosis. Further characterization and evaluation of dogs and cats with lymphoma is required to help understand the mechanism(s) and the clinical significance of these alterations.

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“…We found that PRMT5 knockdown inhibited cell migration and invasion and slowed tumor growth in nude mice. PRMT5 is an emerging epigenetic enzyme that regulates the transcription of target genes through di-methylation of histone residues [ 37 ]. At present, there are highly selective PRMT5 inhibitors developed with PRMT5 as the target, which are used for the treatment of malignant solid tumors and hematological tumors, and have been approved for clinical trials [ 38 ].…”

Section: Discussionmentioning

confidence: 99%

Cullin 4A/protein arginine methyltransferase 5 (CUL4A/PRMT5) promotes cell malignant phenotypes and tumor growth in nasopharyngeal carcinoma

2022

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Targeted therapy is an important therapeutic strategy currently, however, the development of targeted therapy for nasopharyngeal carcinoma (NPC) is relatively lagging. Cullin 4A (CUL4A) was reported to be overexpressed in NPC; nevertheless, the specific role of CUL4A remains unrevealed. NPC cells and tumor-bearing mice were cultivated to explore the role and mechanism of CUL4A in NPC. After evaluating CUL4A levels in NPC cells, functional experiments were carried out to investigate the effects of CUL4A knockdown and overexpression on cell proliferative, invasive and migratory aptitude as well as NF-κB signaling. Following the GeneMANIA database predicted that protein arginine methyltransferase 5 (PRMT5) was downstream of CUL4A, the mediated role of PRMT5 in the regulation of CUL4A on cells was then determined. Moreover, the tumor volumes and weights of tumor-bearing mice were recorded, and the levels of proliferation-, migration-, and NF-κB signaling-related proteins in the tumor were determined. Herein, CUL4A was enhanced in NPC cells, and its knockdown and overexpression separately suppressed and promoted cell proliferative, invasive, and migratory aptitude as well as NF-κB signal activation. Novelty, PRMT5 knockdown reversed the influences of CUL4A overexpression on these aspects. In addition, its knockdown likewise reversed the facilitating impact of CUL4A expression on tumor growth and declined the expression levels of proliferation-, migration-, and NF-κB signaling-related protein in the tumor. Together, this paper indicated that CUL4A promoted the proliferative, invasive, and migratory aptitude of NPC cells as well as tumor growth by promoting PRMT5 to activate NF-κB signaling.

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Validation of protein arginine methyltransferase 5 (PRMT5) as a candidate therapeutic target in the spontaneous canine model of non-Hodgkin lymphoma

Cited by 6 publications

References 63 publications

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

Epigenetic Alterations in Canine Malignant Lymphoma: Future and Clinical Outcomes

The association between symmetric dimethylarginine concentrations and various neoplasms in dogs and cats

Cullin 4A/protein arginine methyltransferase 5 (CUL4A/PRMT5) promotes cell malignant phenotypes and tumor growth in nasopharyngeal carcinoma

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